DESCRIPTION (Taken from application) Hereditary pancreatitis is a chronic, idiopathic inflammatory disorder of the pancreas affecting multiple family members over 2 or more generations. It can be devastating to affected individuals, causing sever, recurrent abdominal pain beginning in early childhood, followed by years of chronic pain, diabetes mellitus and other complications of chronic pancreatitis. Inheritance occurs as an autosomal dominant trait with variable expression. However, the biochemical and genetic bases for hereditary pancreatitis are completely unknown. All of the hypotheses concerning the underlying pathologic mechanisms for hereditary pancreatitis that have been advanced to date have failed rigorous testing. As no new hypotheses have emerged, the introduction of new ideas and new methodologies to the field is of paramount importance. Familial linkage analyses have proved to be extremely powerful tools for the localization of disease gene loci to discrete regions on individual human chromosomes. Therefore the application of this technology to HP promises to provide the first definitive step in our understanding of this devastating disease. The familial linkage project described in the incumbent proposal will benefit from the cooperation of a very large multi-generational family that is affected with hereditary pancreatitis. The aims of this proposal are therefore to accurately characterize all of the clinical features of the affected and unaffected family members. To determine the chromosomal locus of the gene causing hereditary pancreatitis using genetic linkage analysis with well defined microsatallite markers. To perform confirmatory studies in a second unrelated kindred in cooperation with the International Hereditary Pancreatitis Project. And to identify the gene causing hereditary pancreatitis using overlapping YAC contigs, mutational analysis and DNA sequencing. Because of the huge size of this family, several hundred members, it should be possible through recombinational exclusion to rapidly define a very small candidate gene locus thereby greatly reducing the time between mapping and cloning of the HP disease gene. Identification of the gene will lead to an understanding of the disease and new treatment strategies.